CLL involves the proliferation of neoplastic peripheral blood lymphocytes. About 95 percent of CLLs express surface antigens which indicate they are of B-cell origin, while the remaining 5 percent are of T-cell origin.
CLLs of different origins have different clinical presentations and general disease courses. B-cell CLLs generally infiltrate the lymph nodes, bone marrow, and spleen and tend to have a indolent course. In contrast, T-cell CLLs are more malignant/and present additional infiltration in the skin (Freedman et al., Hematol. Oncol. Clinics of N. Am. 4(2):405-456, 1990).
Treatment of CLL is generally individualized. No specific treatment is required in older patients having an indolent form of the disease. However, other patients with more advanced disease or with disease having a more rapid course may have a median survival of less than two years. Therefore, some sort of treatment should be pursued. The majority of patients have an intermediate prognosis, and although they fare reasonably well without treatment for several years, ultimately they will require some form of therapy.
The typical treatment for CLL is the administration of chlorambucil, a chemotherapeutic agent. Combination chemotherapy is generally used only in advanced cases. Radiation therapy has been effectively used, particularly if splenic enlargement is present and bone marrow transplantation has been successful with younger patients (Foon et al., Leukemia 6(Supp. 4):26-32, 1992). More recently, the nucleoside fludarabine, a fluorinated adenine analog, and 2-chlorodeoxyadenosine, a deoxyadenosine analog, have been found to be effective. Both analogs are resistant to deamination (Keating et al., Leukemia 6(Supp. 4):140-141, 1992). All of these therapies focus on elimination (with replacement, in the case of the transplants) of the malignant cells.
Differentiation treatment has been developed for the treatment of leukemias of immature cells, such as acute promyelocytic leukemia (APL). Rather than killing the malignant cells, factors which cause the cells to mature are administered, and as a result, the malignant immature cells mature and lose their neoplastic nature.
It has been found that retinoids, and particularly trans-retinoic acid, are effective in treating APL (Warrell et al. New Eng. J. Med. 324:1385-1393, 1991). The treatment of pediatric acute nonlymphocytic leukemia (ANLL) (Bell et al. J. of Immunother. 10:77-83,1991), acute myeloid leukemia (AML) in elderly patients (Kramer et al. Cancer 67(6):1484-1486, 1991), and cutaneous T- cell lymphoma (CTCL) (Hoting et al. Cancer 62(6) :1044-1048, 1988) with forms of retinoic acid and its analogs has been the subject of clinical studies. However, neither retinoids nor carotinoids such as beta-carotene have been used in the treatment of leukemias involving mature cells, such as with CLL or T-CLL.
Other studies of the use of retinoids and carotinoids in the prevention of various types of cancer have been reported (see, for example, Table 3 of Bertram et al., Cancer Res. 47:3012-3031, 1987). However, these studies have generally concentrated on cancers of the digestive or reproductive systems and do not discuss the treatment of leukemia. For example, Garewal et al., Can. Epid. Biomark. Prev. 1:155-159, 1992, proposed to treat leukoplakia with vitamin A in combination with beta-carotene.
It has now been discovered that beta-carotene therapy is effective in the treatment of established mature cell malignancies such as CLL and T-CLL.